Abstract: Barrett's esophagus (BE), a prelimalignant disease predisposing to human esophageal adenocarcinoma (EAC), is known to predominantly afflict Caucasian Americans. Our preliminary data have shown that in human BE a series of genes and pathways are activated to mediate the process of intestinal metaplasia, and thatintestinal transcription factors (e.g., Cdxl and Cdx2) are crucial to this process. Both Cdx1 and Cdx2 are induced and expressed in esophageal epithelial cells through loss of promoter methylation. Transfection of Cdx2 into human esophageal squamous epithelial cells induces metaplastic changes in morphology and gene expression. In this proposal, we hypothesize that environmental factors, genetic factors, and potentially gene-environment interactions play crucial roles in the observed racial disparity in BE. Clinical data, gastric secretions, endoscopic biopsy samples and blood samples will be collected from Caucasian and African American patients to identify critical environmental and genetic factors leading to BE. We hypothesize that differential distribution of genetic risk factors make Caucasian Americans more susceptible to BE than African Americans. Understanding the pathogenesis of the lesion is vital to future attempts at preventing metaplastic and dysplastic changes in the esophagus.